Variation in FTO contributes to childhood obesity and severe adult obesity

We identified a set of SNPs in the first intron of the FTO (fat mass and obesity associated) gene on chromosome 16q12.2 that is consistently strongly associated with early-onset and severe obesity in both adults and children of European ancestry with an experiment-wise P value of 1.67 x 10(-26) in 2,900 affected individuals and 5,100 controls. The at-risk haplotype yields a proportion of attributable risk of 22% for common obesity. We conclude that FTO contributes to human obesity and hence may be a target for subsequent functional analyses.     

Paraneoplastic myasthenic syndrome IgG inhibits 45Ca2+ flux in a human small cell carcinoma line

Certain cancers exert unexplained remote effects on the nervous system. Small cell carcinoma (SCC) of the lung, a tumour capable of spike electrogenesis and which is of possible neural crest origin, is present in approximately 70% of patients with the Lambert-Eaton myasthenic syndrome (LEMS), a disorder characterized by fatigable muscle weakness. Patients with this syndrome have a defect in the (Ca2+-dependent) quantal release of acetylcholine from motor nerve terminals evoked by a nerve impulse or by high K+ (ref.5), and a decreased number of presynaptic active zone particles. The physiological and morphological features of the syndrome can be transferred to mice by the patients' IgG, consistent with an autoantibody interfering with the function of voltage-dependent Ca2+ channels. Here we demonstrate that K+-induced 45Ca2+ flux in a cultured human SCC line is significantly reduced by LEMS IgG, suggesting that in SCC-LEMS an autoantibody to tumour Ca2+-channel determinants is triggered; its cross-reaction with similar determinants at the motor nerve terminal could lead to the remote neurological syndrome.     

从中国大陆产银环蛇毒纯化的第三个K－神经毒素Ⅱ．功能检测

从中国大陆产银环蛇毒纯化得到两个Ｋ－神经毒素：Ⅵ２６及Ⅷ１ｂ峰，其中Ⅵ２ｄ峰的部分氨基酸顺序与Ｋ－银环蛇毒素结构均一。Ⅵ２６及Ⅷ１ｂ峰在浓度分别为１５０ｎｍｏｌ／Ｌ及２００ｎｍｏｌ／Ｌ经３０分钟可完全阻断小鸡睫状神经节的烟碱传递，表明这两个Ｋ－神经毒素均为高效神经元烟碱乙酰胆碱受体拮抗剂。以Ａｆｆｉ－ｇｅｌ４０１亲和层析柱纯化的电鳐烟碱受体在严格的脂－蛋白比例下重构至人工微团上，以￣（８６）Ｒｂ￣＋内流至荷有烟碱乙酰胆碱受体的囊泡来衡量离子通道功能．测定了α－银环蛇毒素及Ｋ－神经毒素对受体离子内流的抑制作用．毒素（μｍｏｌ）与受体（μｍｏｌ）比值为０．５时，α－银环蛇毒素１００％阻断氨甲酰胆碱作用下的受体离子内流。１０倍于此浓度的Ｋ－神经毒素对离子通道活动无影响。     

Proteases of Antarctic krill—a new system for effective enzymatic debridement of necrotic ulcerations

Summary The Antarctic krill (Euphausia superba) possesses an over-dimensioned digestive system, which is of vital importance for the survival of this euphaucean shrimp in the extreme marine environment. The isolated enzymes contain a well-balanced mixture of both endo- and exopeptidases, assuring fast and complete breakdown of proteinaceous material. These unique properties have now been shown to be extremely valuable for the effective removal of necrotic debris, fibrin or blood crusts in vitro. Therefore the krill enzymes should be considered as an important resource in the future management of necrotic wounds.     

From carrot to clinic: an overview of the retinoic acid signaling pathway

Vitamin A is essential for the formation and maintenance of many body tissues. It is also important for embryonic growth and development and can act as a teratogen at critical periods of development. Retinoic acid (RA) is the biologically active form of vitamin A and its signaling is mediated by the RA and retinoid X receptors. In addition to its role as an important molecule during development, RA has also been implicated in clinical applications, both as a potential anti-tumor agent as well as for the treatment of skin diseases. This review presents an overview of how dietary retinoids are converted to RA, hence presenting the major players in RA metabolism and signaling, and highlights examples of treatment applications of retinoids. Moreover, we discuss the origin and diversification of the retinoid pathway, which are important factors for understanding the evolution of ligand-specificity among retinoid receptors.     

Activation of innate immunity by lysozyme fibrils is critically dependent on cross-β sheet structure

Inflammation occurs in many amyloidoses, but its underlying mechanisms remain enigmatic. Here we show that amyloid fibrils of human lysozyme, which are associated with severe systemic amyloidoses, induce the secretion of pro-inflammatory cytokines through activation of the NLRP3 (NLR, pyrin domain containing 3) inflammasome and the Toll-like receptor 2, two innate immune receptors that may be involved in immune responses associated to amyloidoses. More importantly, our data clearly suggest that the induction of inflammatory responses by amyloid fibrils is linked to their intrinsic structure, because the monomeric form and a non-fibrillar type of lysozyme aggregates are both unable to trigger cytokine secretion. These lysozyme species lack the so-called cross-β structure, a characteristic structural motif common to all amyloid fibrils irrespective of their origin. Since fibrils of other bacterial and endogenous proteins have been shown to trigger immunological responses, our observations suggest that the cross-β structural signature might be recognized as a generic danger signal by the immune system.     

Global trends of whole-genome duplications revealed by the ciliate Paramecium tetraurelia

The duplication of entire genomes has long been recognized as having great potential for evolutionary novelties, but the mechanisms underlying their resolution through gene loss are poorly understood. Here we show that in the unicellular eukaryote Paramecium tetraurelia, a ciliate, most of the nearly 40,000 genes arose through at least three successive whole-genome duplications. Phylogenetic analysis indicates that the most recent duplication coincides with an explosion of speciation events that gave rise to the P. aurelia complex of 15 sibling species. We observed that gene loss occurs over a long timescale, not as an initial massive event. Genes from the same metabolic pathway or protein complex have common patterns of gene loss, and highly expressed genes are over-retained after all duplications. The conclusion of this analysis is that many genes are maintained after whole-genome duplication not because of functional innovation but because of gene dosage constraints.     

RPA regulates telomerase action by providing Est1p access to chromosome ends

Replication protein A (RPA) is a highly conserved single-stranded DNA-binding protein involved in DNA replication, recombination and repair. We show here that RPA is present at the telomeres of the budding yeast Saccharomyces cerevisiae, with a maximal association in S phase. A truncation of the N-terminal region of Rfa2p (associated with the rfa2Delta40 mutated allele) results in severe telomere shortening caused by a defect in the in vivo regulation of telomerase activity. Cells carrying rfa2Delta40 show impaired binding of the protein Est1p, which is required for telomerase action. In addition, normal telomere length can be restored by expressing a Cdc13-Est1p hybrid protein. These findings indicate that RPA activates telomerase by loading Est1p onto telomeres during S phase. We propose a model of in vivo telomerase action that involves synergistic action of RPA and Cdc13p at the G-rich 3' overhang of telomeric DNA.     

Recombination and the Tel1 and Mec1 checkpoints differentially effect genome rearrangements driven by telomere dysfunction in yeast

In telomerase-deficient Saccharomyces cerevisiae, telomeres are maintained by recombination. Here we used a S. cerevisiae assay for characterizing gross chromosomal rearrangements (GCRs) to analyze genome instability in post-senescent telomerase-deficient cells. Telomerase-deficient tlc1 and est2 mutants did not have increased GCR rates, but their telomeres could be joined to other DNAs resulting in chromosome fusions. Inactivation of Tel1 or either the Rad51 or Rad59 recombination pathways in telomerase-deficient cells increased the GCR rate, even though telomeres were maintained. The GCRs were translocations and chromosome fusions formed by nonhomologous end joining. We observed chromosome fusions only in mutant strains expressing Rad51 and Rad55 or when Tel1 was inactivated. In contrast, inactivation of Mec1 resulted in more inversion translocations such as the isochromosomes seen in human tumors. These inversion translocations seemed to be formed by recombination after replication of broken chromosomes.